RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
N-803，一种 IL-15 超级激动剂复合物，作为急性髓系白血病或骨髓增生异常综合征异基因供者干细胞移植后的维持治疗；一项 2 期试验
英文原题：N-803, an IL-15 Superagonist Complex as Maintenance Therapy After Allogeneic Donor Stem Cell Transplant for Acute Myeloid Leukemia or Myelodysplastic Syndrome; A Phase 2 Trial.
查看英文原题
N-803, an IL-15 Superagonist Complex as Maintenance Therapy After Allogeneic Donor Stem Cell Transplant for Acute Myeloid Leukemia or Myelodysplastic Syndrome; A Phase 2 Trial.
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中文摘要
维持治疗可能增强髓系恶性肿瘤患者接受异基因供者造血细胞移植（HCT）后的自然杀伤（NK）细胞免疫监视，是提高治愈率的一种潜在策略。白细胞介素 15（IL-15）可增强淋巴细胞增殖和抗肿瘤活性。
在此前一项针对 HCT 后复发 AML 患者开展的 IL-15 超级激动剂 N-803 I 期研究中，我们观察到体内 NK 细胞扩增及抗肿瘤应答。本 II 期试验的主要目标是确定移植后给予 N-803 能否降低复发。研究在处于完全缓解（CR）的骨髓增生异常综合征（MDS）或急性髓系白血病（AML）患者中，于 HCT 后第 60 天皮下注射（SQ）N-803，剂量为 6 μg/kg，共 20 例（n = 20）。治疗计划分两个连续队列，分别每周、每两周或每 4 周给药。给药后最常见的不良事件为自限性注射部位皮疹（n = 20）。N-803 给药一周后，观察到 NK 细胞增殖增强、抗肿瘤细胞毒性提高，且未诱导免疫耗竭。5 例患者在 N-803 治疗后发生急性移植物抗宿主病（aGVHD），均迅速对类固醇治疗产生应答；另有 4 例发生慢性 GVHD。接受超过 4 次 N-803 给药的患者，两年复发率下降至三分之一（P = .06）。这些发现支持 N-803 用于预防 HSCT 后 AML/MDS 复发具有安全性、免疫激活作用和潜在疗效。
展开英文摘要原文
Maintenance therapy may improve natural killer (NK) cell surveillance after allogeneic donor hematopoietic cell transplant (HCT) for myeloid malignancies and represents a potential approach to improve cure rates. Interleukin-15 (IL-15) enhances lymphocyte proliferation and antitumor activity.
In a prior Phase 1 study of an IL-15 superagonist (N-803) in patients with AML who relapsed after HCT, we observed in vivo expansion of NK cells and antitumor responses. The primary objective of this Phase 2 trial was to determine if post-transplant N-803 could reduce relapse.
We administered N-803 (n = 20) (dosed 6 mcg/kg subcutaneously [SQ] at day 60 after HCT to patients with myelodysplastic syndrome [MDS] or acute myeloid leukemia [AML] who were in complete remission [CR]). N-803 treatment was planned weekly, biweekly or every 4 weeks in 2 sequential cohorts. The most common adverse events after administration were self-limited injection sites skin rashes (n = 20).
One week after an N-803 dose, we observed enhanced NK cell proliferation and improved antitumor cytotoxicity without inducing immune exhaustion. Five patients who developed acute graft versus host disease (aGVHD) after N-803 responded promptly to steroids and 4 patients developed chronic GVHD. Patients receiving >4 doses of N-803 had a 3-fold decrease in relapse at two years (P = . 06).
These findings support the safety, immune activation, and potential efficacy of N-803 to prevent relapse of AML/MDS after HSCT.
论文信息
- 作者
- Merino A、Brunstein CC、Shanley R、Rashid F、Wangen R、Bachanova V、Juckett M、Maakaron J
- 单位
- Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, Minnesota. Electronic address: merin008@umn.edu.United States
- 文献类型
- II 期临床试验 · 美国 NIH 资助研究 · 非美国政府资助研究
- 期刊
- Transplantation and cellular therapy2024 Dec
- 原文标识
- PubMed 39362494 · DOI 10.1016/j.jtct.2024.09.023
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